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PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.
Konttinen, Henna; Cabral-da-Silva, Mauricio E Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W; Vickers, James; Smith, Grady C; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja.
Afiliación
  • Konttinen H; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Cabral-da-Silva MEC; School of Chemistry and Molecular Bioscience, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
  • Ohtonen S; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Wojciechowski S; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Shakirzyanova A; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Caligola S; Department of Computer Science, University of Verona, Verona 37134, Italy.
  • Giugno R; Department of Computer Science, University of Verona, Verona 37134, Italy.
  • Ishchenko Y; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Hernández D; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia; Department of Surgery, the University of Melbourne, Melbourne, VIC 3002, Australia; Department of Anatomy and Neuroscience, the University of Melbourne, Melbourne, VIC 3002, Australia.
  • Fazaludeen MF; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Eamen S; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Budia MG; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Fagerlund I; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Scoyni F; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Korhonen P; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Huber N; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Haapasalo A; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Hewitt AW; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia; Department of Surgery, the University of Melbourne, Melbourne, VIC 3002, Australia; School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, VIC 7005, Australia
  • Vickers J; Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS 7000, Australia.
  • Smith GC; School of Chemistry and Molecular Bioscience, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
  • Oksanen M; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Graff C; Department NVS, Division of Neurogeriatrics, Karolinka Institutet, Stockholm 17176, Sweden; Theme Aging, Genetics Unit, Karolinska University Hospital-Solna, Stockholm 17176, Sweden.
  • Kanninen KM; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Lehtonen S; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • Propson N; Department of Molecular and Cell Biology and the Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
  • Schwartz MP; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Pébay A; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia; Department of Surgery, the University of Melbourne, Melbourne, VIC 3002, Australia; Department of Anatomy and Neuroscience, the University of Melbourne, Melbourne, VIC 3002, Australia.
  • Koistinaho J; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland; Neuroscience Center, University of Helsinki, Helsinki 00014, Finland.
  • Ooi L; School of Chemistry and Molecular Bioscience, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
  • Malm T; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland. Electronic address: tarja.malm@uef.fi.
Stem Cell Reports ; 13(4): 669-683, 2019 10 08.
Article en En | MEDLINE | ID: mdl-31522977
ABSTRACT
Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Diferenciación Celular / Precursor de Proteína beta-Amiloide / Microglía / Apolipoproteína E4 / Presenilina-1 / Células Madre Pluripotentes Inducidas Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2019 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Diferenciación Celular / Precursor de Proteína beta-Amiloide / Microglía / Apolipoproteína E4 / Presenilina-1 / Células Madre Pluripotentes Inducidas Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2019 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA